Saxagliptin, (1S,3S,5S)-2-((2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:
is reported to be a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.
Saxagliptin, and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. Nos. 6,395,767, and 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate.
U.S. 2009/054303 and the corresponding WO 2008/131149 disclose several crystalline forms of Saxagliptin and of Saxagliptin salts. The crystalline forms of Saxagliptin reported in this patent application are a monohydrate (denoted there as form H-1), a hemihydrate (denoted there as form H0.5-2), and an anhydrous form (denoted there as N-3).
WO 2005/117841 (the '841 application) describes the cyclization of Saxagliptin to form the therapeutically inactive cyclic amidine. The '841 application reports that this cyclization can occur both in solid state and solution state.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Saxagliptin, may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) as well as content of solvent in the polymorphic form, which have been used to distinguish polymorphic forms.
The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different polymorphic forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms of Saxagliptin and Saxagliptin intermediates provides new opportunities to improve the synthesis and the characteristics of the active pharmaceutical ingredient (API). It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Therefore, there is a need for additional solid state forms of Saxagliptin and Saxagliptin intermediates, and additional methods for preparing Saxagliptin crystal forms that provide Saxagliptin efficiently, and can be applied in an industrial scale.